bmj open€¦ · for peer review only 17 6. unverdorben m, vallbracht c, cremers b, et al....

For peer review only

Comparison of new-generation drug-eluting stents versus drug-coated balloon for in-stent restenosis: A meta-analysis

of randomized controlled trials

Journal: BMJ Open

Manuscript ID bmjopen-2017-017231

Article Type: Research

Date Submitted by the Author: 12-Apr-2017

Complete List of Authors: Cai, Jin-Zan; cardiology Zhu, Yong-Xiang Bourantas, Christos

Iqbal, Javaid Zhu, Hao Cummins, Paul Dong, Sheng-Jie Mathur, Anthony; Barts Health NHS Trust, Cardiology zhang, yaojun

<b>Primary Subject Heading</b>:

Cardiovascular medicine

Secondary Subject Heading: Cardiovascular medicine

Keywords: Drug-coated balloon, Drug-eluting stents, In-stent restenosis, Meta-analysis

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Title page

Comparison of new-generation drug-eluting stents versus drug-coated balloon for

in-stent restenosis: A meta-analysis of randomized controlled trials

Authors: Jin-Zan Cai1, MSc; Yong-Xiang Zhu

1, MSc; Christos V. Bourantas

3, 4, PhD; Javaid Iqbal

2, PhD; Hao Zhu

1,

MSc; Paul Cummins5, BSc; Sheng-jie Dong

6, PhD; Anthony Mathur

4, PhD; Yao-Jun Zhang

1* PhD

Cai JZ and Zhu YX are equally contributed to this manuscript.

Author Affiliations:

1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China;

2Sheffield Teaching Hospitals and the University of Sheffield, Sheffield, United Kingdom;

3Department of Cardiovascular Sciences, University College London, London, UK;

4Department of Cardiology, Barts Heart Centre, London, UK;

5Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands;

6Department of the Joint and Bone Surgery, Yantaishan hospital, Yantai, China;

Running title: DES versus DCB for ISR

*Correspondence to:

Yao-Jun Zhang MD, PhD, FESC

No. 68, Changle Road, Nanjing, 210006, China

Email: [email protected]; Tel & Fax: +86-025-52271340

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Abstract

Objective: The study sought to compare angiographic and clinical results of new-generation drug-eluting

stents (DES) versus drug-coated balloon (DCB) in patients with coronary in-stent restenosis (ISR).

Design: Meta-analyses using data from randomised trial found by searches on PubMed, the Cochrane Library,

Clinicaltrials.gov, and major cardiovascular congresses.

Setting: Only randomised trials comparing DES with DCB was included.

Participants: Patients with ISR in the including trails.

Interventions: DES or DCB.

Primary and secondary outcomes: The primary outcome were cardiac death, all-cause death, myocardial

infarction, target lesion revascularization (TLR), target vessel revascularization (TVR), major adverse cardiac

events (MACE), and stent thrombosis. Secondary outcomes were angiographic endpoints.

Results: Five trials were eligible and included. Meta-analyses showed that DES had significantly reduced the

risk of target lesion revascularization (TLR, RR: 1.96, 95% CI: 1.17 to 3.28, p=0.01), however no statistical

differences were seen in terms of major adverse cardiac events (MACE, RR: 1.21, 95% CI: 0.67 to 2.17,

p=0.53), myocardial infarction (RR: 1.16, 95% CI: 0.55 to 2.48, p=0.69), and cardiac death (RR: 1.80, 95% CI:

0.60 to 5.39, p=0.29) when compared with DCB. Pooled analyses in angiographic results identified that

new-generation DES were associated with higher acute luminal gain (-0.31 mm, 95% CI: -0.42 to -0.20,

p<0.001) and lower % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04).

Conclusions: Interventions with new-generation DES are associated with significant reductions in % diameter

stenosis and TLR, but similar MACE, myocardial infarction, and cardiac death for coronary ISR patients

compared to DCB. Appropriately powered studies with longer term follow-up are warranted to confirm the

findings from the present meta-analysis.

Keywords: Drug-coated balloon; Drug-eluting stents; In-stent restenosis; Meta-analysis.

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Strengths and limitations of this study

1、 Only randomized trials comparing DES with DCB for patients with ISR were allowed to include in this

meta-analysis.

2、、、、 This study demonstrates the largest patient population presenting with ISR.

3、、、、 The results were based on the trial level and shares the limitations of the original trials.

Introduction

Percutaneous coronary intervention with bare-metal stents (BMS) or drug-eluting stents (DES) has become

one of the most frequently performed therapeutic procedures for coronary artery disease1)

. The rate of

in-stent restenosis (ISR) in clinical practice is nearly 5% of patients treated with DES and 10% with BMS after

5 years2)

. Given the number of patients undergoing a stent implantation, which accounts for approximately

954,000 in USA each year, ISR will continue to be an undesirable adverse entity3)

.

The management of patients with ISR remains challenging to the extent that the therapeutic choices remain

debatable. Currently, the treatment strategies for ISR mainly include cutting balloon angioplasty, plain old

balloon angioplasty, drug-coated balloon (DCB) and DES4)

. Several recent studies have reported that both

new-generation DES and DCB with favorable prognosis are superior to other interventional strategies for

ISR5-12)

. Moreover, recent guidelines on myocardial revascularization from the European Society of Cardiology

recommends DCB and new-generation DES (class I, level A) for patients presenting with ISR1)

. However,

published literature comparing new-generation DES versus DCB in randomized settings conclude with

diverging results8,13-17)

. Additionally, these studies were constrained by the small number of ISR patients

which were inconclusive in terms of clinical outcomes. As a consequence, we performed a meta-analysis of

randomized controlled trials to compare the clinical outcomes and coronary angiographic results of

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new-generation DES with DCB in patients with coronary ISR.

Methods

Search strategy and selection criteria

Randomized trials comparing new-generation DES versus DCB for coronary ISR were searched in PubMed,

the Cochrane Library, and Clinicaltrials.gov as well as major cardiovascular congresses. The subject keywords

included coronary restenosis, drug-eluting balloon, paclitaxel-coated balloon, eluting stent(s), and

randomized trial were applied to identify studies. The last search was performed on September 12th, 2016

by two independent investigators (Cai JZ and Zhu YX). All studies comparing new-generation DES versus DCB

irrespective of patients presenting with any types of ISR were included.

Data extraction and quality assessment

Two investigators (Cai JZ and Zhu YX) independently screened the title and abstract of retrieved reports,

reviewed the full articles of relevant citations in detail, and extracted study characteristics, angiographic, and

longest available clinical outcomes. Any discrepancies or disagreements were settled by a third investigator

(Zhang YJ). The following variables were extracted from all eligible studies: enrollment periods, patient

characteristics, types of ISR, definition of ISR, follow-up duration, dual antiplatelet therapy, and clinical and

angiographic outcomes. The risk of bias for individual trials was assessed in accordance with the Cochrane

Collaboration’s tool18)

.

Angiographic and clinical outcomes

The clinical outcomes of interest were cardiac death, all-cause death, myocardial infarction, target lesion

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revascularization (TLR), target vessel revascularization (TVR), major adverse cardiac events (MACE), and stent

thrombosis. TLR was defined as any repeated revascularization involving the target lesion. MACE was defined

as individual trial. The angiographic endpoints were minimum lumen diameter (MLD), late lumen loss (LLL)

and % diameter stenosis at 6 to 12 months. In-segment (the treated segment plus 5 mm proximal/distal

margins) measurements were adopted for the analyses, but in-stent parameters was incorporated if

in-segment data were not available.

Statistical analysis

Risk ratio (RR) and mean differences with 95% confidence interval (CI) were utilized as summary statistics.

The Mantel-Haenszel fixed-effects model and Inverse Variance fixed-effects model were used for categorical

variables and continuous variables, respectively. We performed the I2 test and chi-square test to evaluate

heterogeneity among studies. An I2 > 50% or p values < 0.10 was considered as significant heterogeneity. A

random-effects model was performed to calculate the risk estimation if a significant heterogeneity was

detected. Sensitivity analyses were carried out by omitting one study at a time. The Egger’s linear regression

tests were employed to test for funnel plot asymmetry at the p<0.10 level of significance. We also repeated

analyses in the subsets of studies solely comparing paclitaxel-coated balloon versus everolimus-eluting stents,

and patients only with BMS-ISR. All the statistical analyses were performed using STATA Version 13.0 (Stata

Corp., College Station, TX, USA) and Review Manager Version 5.3 (The Nordic Cochrane Centre, Copenhagen,

Denmark).

Results

Five trials with a total of 913 patients treated either with new-generation DES (n=414) or DCB (n=499) were

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eligible and included8,13-17)

. The screening process is described in Figure 1. The summary of risk judgment in

individual trials is showed in Supplement Figure 1. The trial, patient and angiographic characteristics are

summarized (Table 1, Supplement Table 1 and 2). Apart from 229 patients (25.1%) with mixed types of ISR in

1 trial17)

, 309 patients (33.9%) with DES-ISR were recruited in 1 trial8)

, while 375 patients (41.0%) with

BMS-ISR were in 3 trials14-16)

. The patients follow up ranged from 6 to 12 months angiographically, and 12 to

36 months clinically.

TLR, TVR, and MACE

TLR was reported in 4 trials including 777 patients8,13,16,17)

. The incidence of TLR in the DCB group (10.9%) was

significantly higher than that in new-generation DES (5.2%) (RR: 1.96, 95% CI: 1.17 to 3.28, p=0.01; I2=32%,

P=0.22; Figure 2A). TVR was not available in the BIOLUX RCT trial17)

. There was no significant difference in the

risk of TVR between DCB and DES (RR: 1.06, 95% CI: 0.48 to 2.34, p=0.89; I2=60%, P=0.06; Figure 2B).

All but the SEDUCE trial reported the rates of MACE16)

. The rates of MACE between DCB (14.7%) and DES

(9.0%) were comparable (RR: 1.21, 95% CI: 0.67 to 2.17, p=0.53; I2=58%, P=0.07; Figure 2C).

Cardiac death, all-cause death, myocardial infarction, and stent thrombosis

Myocardial infarction, stent thrombosis and cardiac death were all available in 5 trials but all-cause death

was not reported in the BIOLUX RCT trial17)

. The pooled RR showed no significant differences in cardiac death

(RR: 1.80, 95% CI: 0.60 to 5.39, p=0.29; I2=0%, P=0.92; Figure 3A) and myocardial infarction (RR: 1.16, 95% CI:

0.55 to 2.48, p=0.69; I2=0%, P=0.76; Figure 3B) between the two arms, as well as all-cause death (RR: 1.50,

95% CI: 0.62 to 3.62, p=0.37; I2=0%, P=0.55) and stent thrombosis (RR: 1.26, 95% CI: 0.39 to 4.04, p=0.70;

I2=0%, P=0.75; Figure 3C).

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Angiographic endpoints

All 5 trials contributed to the angiographic follow-up results. Patients treated with new-generation DES had a

significant increase of acute luminal gain (-0.31 mm, 95% CI: -0.42 to -0.20, p<0.001; I2=52%, p=0.08; Figure

4A) and reduction of % diameter stenosis (RR: 0.28, RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04; I2=72%, P=0.006;

Figure 4B) compared to DCB.

A strong trend towards an increase in MLD (-0.23 mm, 95% CI: -0.47 to 0.01, p=0.06; I2=65%, P=0.02, Figure

5A) was noted in the new-generation DES arm but this difference was not statistically significant compared to

DCB.

All but the BIOLUS RCT trial reported the incidences of binary restenosis. Patients treated with

new-generation DES were associated with a similar risk of binary restenosis (RR: 1.25, 95% CI: 0.57 to 2.75,

p=0.58; I2=56%, P=0.08; Figure 5B) and LLL (-0.06mm, 95% CI: -0.37, 0.25, p=0.71; I

2=80%, P=0.0006; Figure

5C) compared to DCB.

Repeated analyses in the subsets of patient population

In the setting of patients with BMS-ISR13,15,16)

, no significant differences were found in DCB versus

new-generation DES in all angiographic and clinical outcomes except for acute luminal gain (-0.39 mm, 95%

CI: -0.50 to -0.28, p<0.001; I2=0%, p=0.40).

Patients treated exclusively with everolimus-eluting stents had significant low incidence of TLR (RR: 2.64, 95%

CI: 1.35 to 5.18, p=0.005; I2=12%, P=0.32), increased acute luminal gain (-0.32 mm, 95% CI: -0.47 to -0.17,

p<0.001; I2=64%, P=0.04), and superior MLD (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I

2=60%, P=0.06;). But

no statistical differences in other clinical and angiographic outcomes were observed between the 2

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groups8,13,15,16)

.

Publication bias and sensitivity analyses

No publication biases were found in all clinical and angiographic outcomes (Supplement Figure 2). Sensitivity

analyses suggested that the favorable results of new-generation DES were concealed in TLR when the RIBS IV

trial was omitted (RR: 1.49, 95% CI: 0.77 to 2.90, p=0.24; I2=27%, P=0.26). Conversely, DCB was associated

with a high risk of MACE (RR: 1.57, 95% CI: 1.04 to 2.38, p=0.03; I2=19%, P=0.29) as well as an increase in in

MLD (-0.29 mm, 95% CI: -0.55 to -0.03, p=0.03; I2=64%, P=0.04) and binary restenosis (RR: 1.85, 95% CI: 1.11

to 3.10, p=0.02; I2=0%, P=0.99) when the TIS trial was omitted. New-generation DES had a greater MLD when

the BIOLUX RCT trial was excluded (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I2=60%, P=0.06).

Discussion

This meta-analysis included 5 randomized trials examining the angiographic and clinical outcomes of

new-generation DES versus DCB in the treatment of any types of coronary ISR. The study, for the first time,

showed that new-generation DES was associated with an improved angiographic and clinical effectiveness

when compared with DCB irrespective of the types of ISR. The main findings are as follows: (1) new

generation DES had significantly reduced the risk of TLR compared to DCB at the longest available follow-up;

(2) there were no statistical differences in cardiac death, myocardial infarction, and MACE between the two

treatment strategies; (3) New-generation DES was related to favorable angiographic results for coronary ISR

with significant increase of acute luminal gain and reduction in % diameter stenosis at 6 to 12 months

follow-up.

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Previous meta-analyses

The choice of therapeutic methods for coronary ISR remains debatable. Several meta-analyses demonstrated

that DCB and DES had comparable clinical and angiographic results for patients with coronary ISR5,19,20)

.

However obvious pitfalls existed in these studies. Firstly, Mamuti W et al. 20)

combined new-generation DES

and first-generation DES in the same group, whereas cumulative evidence has illustrated the difference in

clinical performance of different generation DES21)

. In the Liou’ study, which compared DES with DCB,

demonstrated no superiority of the new-generation DES with respect to similar clinical parameters in the

overall analysis. Regrettably, they included four observational studies in which an inequality of baseline

characteristics was observed19)

. A further limitation of this meta-analysis was minimal number of patients

(n=548) in the 3 randomised trials19)

. Additionally, in a Bayesian network meta-analysis comparing the

performance of all therapeutic treatments for ISR, everolimus-eluting stent was considered as optimal

strategy with pronounced improvements in terms of clinical outcomes6. Nevertheless, the effect was

transitive and mainly derived from indirect comparison5)

. In the present meta-analysis, we, for the first time,

included only randomized trials of new generation DES in comparison with DCB, so the possibility of

confounders influencing estimates for various endpoints is less likely. Furthermore, this meta-analysis

included the largest number of ISR patients to date and demonstrated that contemporary DES with improved

design was associated with favorable outcomes and a lower risk of re-intervention at mid-term follow-up

compared to DCB.


Compared with DCB, new-generation DES were related to favorable prognosis for coronary ISR with superior

angiographic outcomes and reduced TLR. The advantages of new-generation DES comprised of persistent

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radial strength which prevents acute or subacute prolapse of the disrupted plaque and elastic recoil of the

vessel wall, sufficient antiproliferative drugs, and subsequent excellent neointimal hyperplasia inhibition

compared with DCB8,22)

. In the present study, we found that the key angiographic parameters analysed were

in favor of new generation DES in treatment with ISR patients.

Although one may argue that DES add one more stent layer in the finite lesion segment, 80-100 μm of lumen

loss due to the implants seems negligible when considering that new generation DES assumes less

re-intervention. Alternatively, one may express concern regard the long-term safety of stent implantation as

studies have shown that the vascular inflammatory response with the thin-strut platform profile and also its

biocompatibility or biodegradable polymer were extremely low4,21,23)

. The present study, however, remains

limited by its small sample size and short periods of follow-up. By virtue of previously published literature, it

is reasonable to assume that the benefit of new generation DES will remain consistent.

In the RIBS V trial13,14)

, the authors have observed 1 TLR events in the EES group and 2 in the DCB group from

1 to 3 years. In the RESTENT-ISR (Prospective Randomized Comparison of Clinical and Angiographic

Outcomes Between Everolimus-eluting vs. Zotarolimus-eluting Stents for Treatment of Coronary Restenosis

in Drug-Eluting Stents: Intravascular Ultrasound Volumetric Analysis) trial, Hong et al. reported an

approximate rate of 6.0% in late (>1 year) TLR in patients with ISR treated with everolimus-eluting stents and

zotarolimus-eluting stents24)

, similar to several subgroups from all-comers study25,26)

. Similarly, rates of TLR

after 1 year of DCB angioplasty were varied between 0% to 10%6,7,11,12)

. Thus, whether the potential

long-term benefit of DCB compared to addition stent implantation remains to be seen27)

.

The limitations of the current study are henceforth highlighted. Firstly, The RIBS IV trial contributed

significantly in the endpoint of TLR in favor of DES on the basis of our sensitivity analysis11)

. Moreover, our

study presented high heterogeneities in the majority of angiographic and clinical outcomes, which were

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mainly driven by the TIS trial15)

. The investigators elucidated that more severe ISR lesions (regarding both

minimal lumen diameter and percent diameter stenosis) and frequently unfavorable pattern (regarding type

of occlusion and proliferative) allocated in the new-generation DES group could be confounding factors28)

29)

.

In addition, the proportion of usage of scoring balloon pre-dilation, which may have a potential role in

improving the anti-proliferation potency of DCB30)

, were significant higher in the DCB group15,28)

. Therefore,

further researches with a careful follow-up protocol and large sample size should be performed to provide

more confirmative information.

Future perspectives

Currently, new-generation DES represents a superior treatment strategy with similar safety and improved

angiographic and clinical efficacy. We recommends that it should be considered as one of primary treatment

options for coronary ISR. Although new-generation DES reduce the possibility of recurrent ISR, the risk

remains high as multilayers of metal stents in the vessel wall will entail difficulty in further treatments and an

inherent poorer clinical prognosis31)

. Bioresorbable scaffold (BRS) with proven safety and efficacy profiles for

ISR while avoiding in the mid-long term an additional metal layer may be an alternative treatment choice in

the future32,33)

. The ongoing AbsorbISR (Absorb Bioresorbable Scaffold vs. Drug Coated Balloon for Treatment of

In-Stent-Restenosis, NCT02474485) trial comparing bioresorbable vascular scaffold with DCB to treat ISR will

shed light in terms of clinical utility of BRS for coronary ISR. However for patients with intolerable long-term

dual antiplatelet therapy or high risk of bleeding, DCB may be more suitable. Furthermore, researchers

should pursue further optimization of DCB and its auxiliary strategy34,35)

, such as use of scoring balloon before

DCB30)

.

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Limitations

The following potential limitations of the present study are acknowledged. Firstly, the results were based on

the trial level and shares the limitations of the original trials. Secondly, the imbalance of baseline

characteristics may have had led to bias. Thirdly, the studied DCB group included Sequent PleaseTM

and

Pantera LuxTM

paclitaxel-eluting balloons, which have different coatings design, as well as the implemental

methods of DCB in individual trials10)

.Fourthly, the definitions of clinical and angiographic parameters were

not identical in some studies. Finally, in light of the fairly highly selected criteria in our study, only a total of

912 patients were enrolled. However, our study demonstrates the largest patient population presenting with

ISR and is likely to remain the most powerful evidence base for evaluation of DCB versus new-generation

DES.

Conclusions

New-generation DES seems an acceptable treatment strategy with comparable safety and favorable

angiographic and clinical efficacy compared to DCB for coronary ISR. But either new generation DES or DCB

should be recommended as the first choice in the setting of patients with ISR still relies on further larger

scale, longer-term follow-up and randomized trials.

Contributors: ZYJ is the guarantor. ZYJ, CJZ, ZYX, ZH, BC, DXJ and IJ conceived the study design. CJZ, ZYX, ZH

and MA performed the report screening, study inclusion, data extraction. CP, MA, DXJ and ZH analysis the data. ZYJ,

CJZ, ZYX, BC, IJ, CP and MA drafted the manuscript. CP, MA, DXJ and ZH reviewed the manuscript for important

intellectual content. All authors have significantly contributed to the design of study, analysis of data and

drifting or revising manuscript. All authors have read and approved this article.

Funding: This work was supported by Medical Science and technology development Foundation, Nanjing

Department of Health [YKK15100], and Key Project of Nanjing Science and Technology Development

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Foundation [201503024]. For the others authors none were declared.

Competing interests: The authors declare that there is no conflict of interest.

Data sharing statement: no additional data are available.

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Drug-Eluting Stent Restenosis: 3-Year Results of a Randomized Controlled Trial. JACC Cardiovasc Interv 2015; 8: 877-84.

12. Xu B, Qian J, Ge J, et al. Two-year results and subgroup analyses of the PEPCAD China in-stent restenosis trial: A prospective,

multicenter, randomized trial for the treatment of drug-eluting stent in-stent restenosis. Catheter Cardiovasc Interv 2016; 87

Suppl 1: 624-9.

13. Alfonso F, Pérez-Vizcayno MJ, García DBB, et al. Long-Term Results of Everolimus-Eluting Stents Versus Drug-Eluting

Balloons in Patients With Bare-Metal In-Stent Restenosis: 3-Year Follow-Up of the RIBS V Clinical Trial. JACC Cardiovasc

Interv 2016; 9: 1246-55.

14. Alfonso F, Pérez-Vizcayno MJ, Cárdenas A, et al. A randomized comparison of drug-eluting balloon versus everolimus-eluting

stent in patients with bare-metal stent-in-stent restenosis: the RIBS V Clinical Trial (Restenosis Intra-stent of Bare Metal Stents:

paclitaxel-eluting balloon vs. everolimus-eluting stent). J Am Coll Cardiol 2014; 63: 1378-86.

15. Pleva L, Kukla P, Kusnierova P, Zapletalova J, Hlinomaz O. Comparison of the Efficacy of Paclitaxel-Eluting Balloon

Catheters and Everolimus-Eluting Stents in the Treatment of Coronary In-Stent Restenosis: The Treatment of In-Stent

Restenosis Study. Circ Cardiovasc Interv 2016; 9: e003316.

16. Adriaenssens T, Dens J, Ughi G, et al. Optical coherence tomography study of healing characteristics of paclitaxel-eluting

balloons vs. everolimus-eluting stents for in-stent restenosis: the SEDUCE (Safety and Efficacy of a Drug elUting balloon in

Coronary artery rEstenosis) randomised clinical trial. EuroIntervention 2014; 10: 439-48.

17. Naber CK. Clinical performance of the Pantera Lux paclitaxel coated balloon vs. the drug-eluting Orsiro hybrid stent system in

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patients with in-stent restenosis: a randomised controlled trial. Available at:

http://www.pcronline.com/EuroPCR/EuroPCR-2016/DEB-for-in-stent-restenosis-and-de-novo-lesions. Accessed Nov 17, 2016.

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Treatment of In-stent Restenosis: A Systematic Review and Meta-analysis. Heart Lung Circ 2016 .

20. Mamuti W, Ablimit A, Kelimu W, et al. Comparison of drug-eluting balloon versus drug-eluting stent in patients with in-stent

restenosis: insight from randomized controlled trials. Int J Cardiol 2015; 179: 424-9.

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Comprehensive Network Meta-Analysis. J Am Coll Cardiol 2015; 65: 2496-507.

22. Waksman R, Pakala R. Drug-eluting balloon: the comeback kid. Circ Cardiovasc Interv 2009; 2: 352-8.

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TARGET I trial. Int J Cardiovasc Imaging 2015; 31: 1489-96.

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ultrasound volumetric analysis (RESTENT-ISR trial). Eur Heart J 2016 .

25. Richardt G, Leschke M, Abdel-Wahab M, et al. Clinical outcomes of the Resolute zotarolimus-eluting stent in patients with

in-stent restenosis: 2-year results from a pooled analysis. JACC Cardiovasc Interv 2013; 6: 905-13.

26. Campo G, Punzetti S, Malagù M, Ferrari R, Valgimigli M. Two-year outcomes after first- or second-generation drug-eluting

stent implantation in patients with in-stent restenosis. A PRODIGY trial substudy. Int J Cardiol 2014; 173: 343-5.

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Treatment of In-Stent Restenosis Study". Circ Cardiovasc Interv 2016; 9 .

29. Habara S, Kadota K, Shimada T, et al. Late Restenosis After Paclitaxel-Coated Balloon Angioplasty Occurs in Patients With

Drug-Eluting Stent Restenosis. J Am Coll Cardiol 2015; 66: 14-22.

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in-stent restenosis lesions. EuroIntervention 2013; 9: 788-96.

32. Moscarella E, Ielasi A, Granata F, et al. Long-Term Clinical Outcomes After Bioresorbable Vascular Scaffold Implantation for

the Treatment of Coronary In-Stent Restenosis: A Multicenter Italian Experience. Circ Cardiovasc Interv 2016; 9: e003148.

33. Jamshidi P, Nyffenegger T, Sabti Z, et al. A novel approach to treat in-stent restenosis: 6- and 12-month results using the

everolimus-eluting bioresorbable vascular scaffold. EuroIntervention 2016; 11: 1479-86.

34. Scheller B, Fontaine T, Mangner N, et al. A novel drug-coated scoring balloon for the treatment of coronary in-stent restenosis:

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51-9.

35. Verheye S, Vrolix M, Kumsars I, et al. Sirolimus Eluting Angioplasty Balloon for In-Stent Restenosis SABRE Trial: 6 Month

Clinical and Angiographic Results. Available at:

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Table

Table 1 Main characteristics of the included trials

Study Type Treatment arms Sampl

e size

Definition

of ISR

Follow-up, months DAPT,

months Definition of MACE

Angiograph

ic Clinical DCB DES

TIS BMS SP

PCB PE EES 68/68 ≥50% DS 12 12 3 6-12 Death, any MI, and TVR

RIBS IV DES SP

PCB XP EES

154/15

5 ≥50% DS 9 12 3 12 Death, MI, and TLR

SEDUCE BMS SP

PCB XP EES 25/25 >70% DS 9 12 n/a n/a n/a

RIBS V BMS SP

PCB XP EES 95/94 ≥50% DS 9 36 3 12 Death, MI, and TLR

BILUX

RCT Both PL PCB

Orsiro

SES 157/72 n/a 6 12 n/a n/a

Cardiac death, MI, and

TLR

Abbreviations: BMS = bare-metal stents; CAG = coronary angiography; DAPT = dual antiplatelet therapy; DCB =

drug-eluting balloon; DES = drug-eluting stents; DS=diameter stenosis; ISR=in-stent restenosis; MACE = major adverse

cardiac events; MI = myocardial infarction; n/a = not available; PE EES = Promus Element everolimus-eluting stents; PL PCB

= Pantera Lux paclitaxel-coated balloon; SES = sirolimus-eluting balloon; SP PCB = SeQuent Please paclitaxel-coated

balloon; TLR = target lesion revascularization; TVR = target vessel revascularization; XP EES = Xience Prime

everolimus-eluting stent.

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Figure legends

Figure 1

Title: Flow diagram of meta-analysis

Figure 2

Title: Forest plots of risk ratios for TLR, TVR and MACE

Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) TLR,

(B) TVR, and (C) MACE.

Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse

cardiac events; TLR = target lesion revascularization; TVR= target vessel revascularization.

Figure 3

Title: Forest plots of risk ratios for MI, cardiac death, and stent thrombosis

Caption: Size of data markers indicates weight of each trial: (A) MI, (B) cardiac death, (C) stent

thrombosis.

Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MI = myocardial infarction.

Figure 4

Title: Forest plots of risk ratios for acute lumen gain and % diameter stenosis.

Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute

lumen gain, and (B) % DS.

Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; DS = diameter stenosis.

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Figure 5

Title: Forest plot of risk ratios for MLD, Binary restenosis, and LLL.

Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD,

(B) binary restenosis, and (C) LLL.

Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen

diameter; LLL = late lumen loss.

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Figure 1 Title: Flow diagram of meta-analysis

179x155mm (300 x 300 DPI)

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Figure 2 Title: Forest plots of risk ratios for TLR, TVR and MACE

Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) TLR, (B) TVR,

and (C) MACE. Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse cardiac

events; TLR = target lesion revascularization; TVR= target vessel revascularization.

254x190mm (300 x 300 DPI)

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Figure 3 Title: Forest plots of risk ratios for MI, cardiac death, and stent thrombosis

Caption: Size of data markers indicates weight of each trial: (A) MI, (B) cardiac death, (C) stent thrombosis.


254x190mm (300 x 300 DPI)

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Figure 4 Title: Forest plots of risk ratios for acute lumen gain and % diameter stenosis.

Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute lumen gain, and (B) % DS.


254x124mm (300 x 300 DPI)

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Figure 5 Title: Forest plot of risk ratios for MLD, Binary restenosis, and LLL.

Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD, (B) binary restenosis, and (C) LLL.

Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen diameter; LLL = late lumen loss.

254x185mm (300 x 300 DPI)

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Supplement

Figure 1

Title: Risk of bias

Caption: Proportions of studies classified as having low (green), unclear (yellow), and high (red) risk of bias across domains of study quality.

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2

Figure 2

Title: Publication biases.

Caption: The Egger’s liner regression tests for (A) target lesion revascularization, (B) target vessel revascularization, (C) major adverse cardiac

events, (D) myocardial infarction, (E) cardiac death, and (F) stent thrombosis.

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Table 1 Patient characteristics

Study Age Male Hypertension

Diabetes

mellitus Dyslipidemia Previous MI Multi-vessel

DCB DES DCB DES DCB DES DCB DES DCB DES DCB DES DCB DES

TIS 66 (11) 66 (11) 43 (63) 46 (68) n/a n/a 17 (25) 18 (26) n/a n/a 43 (63) 41 (60) 38 (56) 41 (60)

RIBS IV 66 (10) 66 (10) 127

(82)

130

(84)

110

(71)

121

(78) 75 (49) 66 (43)

110

(71)

121

(78) 73 (47) 77 (50) n/a n/a

SEDUCE 68 (8) 64 (11) 18 (72) 25

(100) 16 (64) 15 (60) 6 (24) 1 (4) 24 (96) 24 (96) 12 (48) 10 (40) n/a n/a

RIBS V 67 (11) 64 (12) 82 (86) 82 (87) 68 (72) 68 (72) 30 (32) 19 (20) 69 (73) 62 (66) 57 (60) 56 (60) n/a n/a

BILUX

RCT 67 (10) 69 (9)

122

(78) 49 (68)

144

(92) 70 (97) 48 (31) 24 (33)

134

(85) 62 (86) 93 (59) 35 (49) 95 (61) 39 (54)

Values are mean (SD) or n (%).

Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; EES = everolimus-eluting stents; n/a = not available; MI

= myocardial infarction.

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Table 2 Angiographic characteristics

Study length of pre-stent Mehran III-IV Pre-%DS Pre-MLD Pre-RVD

DCB DES DCB DES DCB DES DCB DES DCB DES

TIS 23 (12) 19 (9) 10 (13) 18 (24) 72 (14) 78 (13) 0.92

(0.5)

0.79

(0.5)

2.64

(0.5)

2.66

(0.5)

RIBS IV 10 (6) 11 (5) 4 (3) 12 (8) 69 (17) 72 (15) 0.79

(0.4)

0.75

(0.4)

2.59

(0.5)

2.67

(0.5)

SEDUCE 20 (n/a) 18 (n/a) 4 (16) 6 (24) 68 (18) 79 (14) 0.98

(0.6)

0.57

(0.4) 3.0 (0.5)

2.85

(0.4)

RIBS V 14 (7) 14 (7) 12 (13) 18 (19) 61 (14) 65 (13) 1.02

(0.4)

0.93

(0.4)

2.64

(0.6)

2.64

(0.6)

BIOLUX

RCT n/a n/a 20 (12) 12 (15) 67 (14) 69 (15) 1.0 (0.5) 0.9 (0.5) 3.0 (0.4) 2.9 (0.5)

Values are mean (SD).

Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; DS = diameter stenosis; MLD = minimum lumen

diameter; RVD = reference vessel diameter; n/a = not available.

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PRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 ChecklistPRISMA 2009 Checklist

Section/topic # Checklist item Reported on page #

TITLE

Title 1 Identify the report as a systematic review, meta-analysis, or both. 1

ABSTRACT

Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.

2

INTRODUCTION

Rationale 3 Describe the rationale for the review in the context of what is already known. 3

Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

3

METHODS

Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,

language, publication status) used as criteria for eligibility, giving rationale. 4

Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

4

Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

4

Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,

included in the meta-analysis). 4

Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

4

Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

4

Risk of bias in individual studies

12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

4-5

Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 4-5

Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I

2) for each meta-analysis.

4-5

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Page 1 of 2


Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

4-5

Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

4-5

RESULTS

Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

5-6

Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

5-6

Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 5-6

Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

6-7

Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 6-7

Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 8

Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 8

DISCUSSION

Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

8-11

Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

11

Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 12

FUNDING

Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.

12

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit: www.prisma-statement.org.

Page 2 of 2

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Comparison of new-generation drug-eluting stents versus

drug-coated balloon for in-stent restenosis: A meta-analysis of randomized controlled trials

Journal: BMJ Open

Manuscript ID bmjopen-2017-017231.R1


Date Submitted by the Author: 18-Aug-2017

Complete List of Authors: Cai, Jin-Zan; Nanjing First Hospital, Nanjing Medical University Zhu, Yong-Xiang ; Nanjing First Hospital, Nanjing Medical University, Department of Cardiology Wang, Xin-Yu; Xuzhou Cancer Hospital, Jiangsu University, Department of Cardiology Bourantas, Christos ; University College London, Cardiovascular Sciences Iqbal, Javaid; Barts Heart Centre, Department of Cardiology Zhu, Hao; Nanjing First Hospital, Nanjing Medical University,, Department of Cardiology

Cummins, Paul ; Erasmus MC, Rotterdam, Department of Cardiology Dong, Sheng-Jie; Yantaishan hospital, Department of the Joint and Bone Surgery Mathur, Anthony; Barts Health NHS Trust, Cardiology zhang, yaojun; Xuzhou Cancer Hospital, Jiangsu University, Department of Cardiology,






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Title page




1, MSc; Xin-Yu Wang

2, BSc; Christos V. Bourantas

3, 4, PhD; Javaid

Iqbal5, PhD; Hao Zhu

1, MSc; Paul Cummins

6, BSc; Sheng-jie Dong


4, PhD; Yao-Jun

Zhang2* PhD

Cai JZ, Zhu YX, and Wang XY are equally contributed to this manuscript.


1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China;

2Department of Cardiology, Xuzhou Cancer Hospital, Jiangsu University, Xuzhou, China;







*Correspondence to:


No. 131, Huancheng Road, Xuzhou, 221005, China


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Abstract

Objective: The study sought to compare angiographic and clinical results of new-generation drug-eluting


Design: Meta-analyses using data from randomised trial found by searches on PubMed, the Cochrane Library,

Clinicaltrials.gov, and major cardiovascular congresses.


Participants: Patients with ISR in the including trails.

Interventions: new-generation DES or DCB.

Primary and secondary outcomes: The angiographic and clinical outcomes including cardiac death, all-cause

death, myocardial infarction, target lesion revascularization (TLR), target vessel revascularization (TVR), major

adverse cardiac events (MACE), and stent thrombosis were investigated.

Results: Five trials including 913 patients were eligible and included. Meta-analyses showed that DES had

significantly reduced the risk of target lesion revascularization (TLR, RR: 1.96, 95% CI: 1.17 to 3.28, p=0.01),

however no statistical differences were seen in terms of major adverse cardiac events (MACE, RR: 1.21, 95%

CI: 0.67 to 2.17, p=0.53), myocardial infarction (RR: 1.16, 95% CI: 0.55 to 2.48, p=0.69), and cardiac death (RR:

1.80, 95% CI: 0.60 to 5.39, p=0.29) when compared with DCB. Pooled analyses in angiographic results

identified that new-generation DES were associated with higher acute luminal gain (-0.31 mm, 95% CI: -0.42

to -0.20, p<0.001) and lower % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04).

Conclusions: Interventions with new-generation DES appeared to be associated with significant reductions

in % diameter stenosis and TLR at short-term follow-up, but similar MACE, myocardial infarction, and cardiac

death for coronary ISR patients compared to DCB. Appropriately powered studies with longer term follow-up

are warranted to confirm the findings from the present meta-analysis.

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meta-analysis.

2、、、、 This study demonstrates the largest patient population presenting with ISR.

3、、、、 The results were based on the trial level and shares the limitations of the original trials.

Introduction


one of the most frequently performed therapeutic procedures for coronary artery disease(1). The rate of


5 years(2). Given the number of patients undergoing a stent implantation, which accounts for approximately

954,000 in USA each year, ISR will continue to be an undesirable adverse entity(3).

The management of patients with ISR remains challenging to the extent that the therapeutic choices remain

debatable. Currently, the treatment strategies for ISR mainly include cutting balloon angioplasty, plain old

balloon angioplasty, drug-coated balloon (DCB) and DES(4). Several recent studies have reported that both

new-generation DES and DCB with favorable prognosis are superior to other interventional strategies for

ISR(5-12). Moreover, recent guidelines on myocardial revascularization from the European Society of

Cardiology recommends DCB and new-generation DES (class I, level A) for patients presenting with ISR(1).

However, published literature comparing new-generation DES versus DCB in randomized settings conclude

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with diverging results(8, 13-17). Additionally, these studies were constrained by the small number of ISR

patients which were inconclusive in terms of clinical outcomes. As a consequence, we performed a

meta-analysis of randomized controlled trials to compare the clinical outcomes and coronary angiographic

results of new-generation DES with DCB in patients with coronary ISR.

Methods



the Cochrane Library, and Clinicaltrials.gov as well as major cardiovascular congresses. The subject keywords

included coronary restenosis, drug-eluting balloon, paclitaxel-coated balloon, eluting stent(s), and

randomized trial were applied to identify studies. The last search was performed on September 12th, 2016

by two independent investigators (Cai JZ and Zhu YX). All studies comparing new-generation DES versus DCB

irrespective of patients presenting with any types of ISR were included.








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Collaboration’s tool(18).












variables and continuous variables, respectively. We calculated the I2 index and performed chi-square test to

measure statistical heterogeneity among studies. An I2 > 50% or p values < 0.10 was considered as significant

heterogeneity. A random-effects model was performed to calculate the risk estimation if a significant

heterogeneity was detected. Sensitivity analyses were carried out by omitting one study at a time, excluding

the studies with a high level of risk of bias, and including only studies with a low proportion of missing data.

The Egger’s linear regression tests were employed to test for funnel plot asymmetry at the p<0.10 level of

significance. However, the analysis for publication bias can only be tentative, as there is not enough power to

support the test results due to the limited number of studies included. We also repeated analyses in the

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subsets of studies solely comparing paclitaxel-coated balloon versus everolimus-eluting stents, and patients

only with BMS-ISR. All the statistical analyses were performed using STATA Version 13.0 (Stata Corp., College

Station, TX, USA) and Review Manager Version 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark).

Results


eligible and included(8, 13-17). The screening process is described in Figure 1. The median and interquartile

range of sample size were 189 and 176 respectively. Only the TIS trail was single center, and the others were

multicentre. Patients enrolled were from Czech in TIS trial, Spain in RIBS IV and RIBS V trials, Belgium in

SEDUCE trial, and Germany and Latvia in BIOLUX RCT. All trial had a high risk of bias with respect to

performance bias and the details of methodology in BIOLUX RCT trial was not available. The summary of risk

judgment in individual trials is showed in Supplement Figure 1. The trial, patient and angiographic

characteristics are summarized (Table 1, Supplement Table 1 and 2). Apart from 229 patients (25.1%) with

mixed types of ISR in 1 trial(17), 309 patients (33.9%) with DES-ISR were recruited in 1 trial(8), while 375

patients (41.0%) with BMS-ISR were in 3 trials(14-16). The patients follow up ranged from 6 to 12 months

angiographically, and 12 to 36 months clinically.

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Table



e size

Definition

of ISR



Angiograph

ic Clinical DCB DES

TIS BMS SP


RIBS IV DES SP

PCB XP EES

154/15


SEDUCE BMS SP


RIBS V BMS SP


BILUX

RCT Both PL PCB

Orsiro

SES 157/72 n/a 6 12 n/a n/a


TLR






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Target lesion revascularization, target vessel revascularization, major adverse cardiac events

TLR was reported in 4 trials including 777 patients(8, 13, 16, 17). The incidence of TLR in the DCB group

(10.9%) was significantly higher than that in new-generation DES (5.2%) (RR: 1.96, 95% CI: 1.17 to 3.28,

p=0.01; I2=32%, P=0.22; Figure 2A). TVR was not available in the BIOLUX RCT trial(17). There was no

significant difference in the risk of TVR between DCB and DES (RR: 1.06, 95% CI: 0.48 to 2.34, p=0.89; I2=60%,

P=0.06; Figure 2B).

All but the SEDUCE trial reported the rates of MACE(16). The rates of MACE between DCB (14.7%) and DES




was not reported in the BIOLUX RCT trial(17). The pooled RR showed no significant differences in cardiac

death (RR: 1.80, 95% CI: 0.60 to 5.39, p=0.29; I2=0%, P=0.92; Figure 3A) and myocardial infarction (RR: 1.16,

95% CI: 0.55 to 2.48, p=0.69; I2=0%, P=0.76; Figure 3B) between the two arms, as well as all-cause death (RR:

1.50, 95% CI: 0.62 to 3.62, p=0.37; I2=0%, P=0.55) and stent thrombosis (RR: 1.26, 95% CI: 0.39 to 4.04,

p=0.70; I2=0%, P=0.75; Figure 3C).




4A) and reduction of % diameter stenosis (RR: 0.28, RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04; I2=72%, P=0.006;

Figure 4B) compared to DCB.

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DCB.




2=80%, P=0.0006; Figure




analyses suggested that the favorable results of new-generation DES were concealed in TLR when the RIBS IV

trial was omitted (RR: 1.49, 95% CI: 0.77 to 2.90, p=0.24; I2=27%, P=0.26). Conversely, DCB was associated

with a high risk of MACE (RR: 1.57, 95% CI: 1.04 to 2.38, p=0.03; I2=19%, P=0.29) as well as an increase in in

MLD (-0.29 mm, 95% CI: -0.55 to -0.03, p=0.03; I2=64%, P=0.04) and binary restenosis (RR: 1.85, 95% CI: 1.11

to 3.10, p=0.02; I2=0%, P=0.99) when the TIS trial was omitted. New-generation DES remains a greater MLD

when the BIOLUX RCT trial was omitted (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I2=60%, P=0.06).

Repeated analyses in the subsets of patient population

In the setting of patients with BMS-ISR(13, 15, 16), no significant differences were found in DCB versus

new-generation DES in all angiographic and clinical outcomes except for acute luminal gain (-0.39 mm, 95%

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CI: -0.50 to -0.28, p<0.001; I2=0%, p=0.40).

Patients treated exclusively with everolimus-eluting stents had significant low incidence of TLR (RR: 2.64, 95%

CI: 1.35 to 5.18, p=0.005; I2=12%, P=0.32), increased acute luminal gain (-0.32 mm, 95% CI: -0.47 to -0.17,

p<0.001; I2=64%, P=0.04), and superior MLD (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I

2=60%, P=0.06;). But

no statistical differences in other clinical and angiographic outcomes were observed between the 2 groups(8,

13, 15, 16).

Discussion



showed that new-generation DES appealed to associated with an improved angiographic and clinical

effectiveness when compared with DCB irrespective of the types of ISR at short term follow-up. The main

findings are as follows: (1) new generation DES had significantly reduced the risk of TLR compared to DCB at

the longest available follow-up; (2) there were no statistical differences in cardiac death, myocardial

infarction, and MACE between the two treatment strategies; (3) New-generation DES was related to

favorable angiographic results for coronary ISR with significant increase of acute luminal gain and reduction

in % diameter stenosis at 6 to 12 months follow-up.



that DCB and DES had comparable clinical and angiographic results for patients with coronary ISR(5, 19, 20).

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However obvious pitfalls existed in these studies. Firstly, Mamuti W et al.(20) combined new-generation DES


clinical performance of different generation DES(21). In the Liou’ study, which compared DES with DCB,

demonstrated no superiority of the new-generation DES with respect to similar clinical parameters in the

overall analysis. Regrettably, they included four observational studies in which an inequality of baseline

characteristics was observed(19). A further limitation of this meta-analysis was minimal number of patients

(n=548) in the 3 randomised trials(19). Additionally, in a Bayesian network meta-analysis comparing the

performance of all therapeutic treatments for ISR, everolimus-eluting stent was considered as optimal

strategy with pronounced improvements in terms of clinical outcomes6. Nevertheless, the effect was

transitive and mainly derived from indirect comparison(5). In the present meta-analysis, we, for the first time,

included only randomized trials of new generation DES in comparison with DCB, so the possibility of

confounders influencing estimates for various endpoints is less likely. Furthermore, this meta-analysis

included the largest number of ISR patients to date and demonstrated that contemporary DES with improved

design was associated with favorable outcomes and a lower risk of re-intervention at mid-term follow-up

compared to DCB.






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compared with DCB(8, 22). Interestingly, the rate of recurrent binary restenosis was similar in two groups.

The difference of TLR was possibly related to the factor that presence of an existing additional stent layer in

the DES group discouraged the operator from repeat intervention.



re-intervention. Alternatively, one may express concern regard the long-term safety of stent implantation as


biocompatibility or biodegradable polymer were extremely low(4, 21, 23). The present study, however,

remains limited by its small sample size and short periods of follow-up. By virtue of previously published

literature, it is reasonable to assume that the short term (less than 1 year) benefit of new generation DES will

remain consistent.

In the RIBS V trial(13, 14), the authors have observed 1 TLR events in the EES group and 2 in the DCB group

from 1 to 3 years. In the RESTENT-ISR (Prospective Randomized Comparison of Clinical and Angiographic




zotarolimus-eluting stents(24), similar to several subgroups from all-comers study(25, 26). Similarly, rates of

TLR after 1 year of DCB angioplasty were varied between 0% to 10%(6, 7, 11, 12). The ISAR-DESIRE 3 and

PEPCAD China trials have shown a late mortality benefit of DCB treatment vs. first generation DES treatment

on longer follow up times. On the other hand, there were similar death in the EES group and DCB group from

1 to 3 years in the RIBS V trial. Thus, whether the potential long-term benefit of DCB compared to addition

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stent implantation remains to be seen(27) .

The limitations of the current study are henceforth highlighted. Firstly, The RIBS IV trial contributed

significantly in the endpoint of TLR in favor of DES on the basis of our sensitivity analysis(11) . The RIBS IV and

RIBS V trial, which account for nearly 64% of studied patient populations in this meta-analysis, allowed acute

pre-dilatation residual stenosis of up to 50 % before DCB application. This is in strong opposition to what is

accepted by most high volume DCB centers and published as the German Consensus Recommendations(10).

Therefore, it is clear that lower acute gains of DCB treatment arm in these 2 trials were documented

compared to other trials. Moreover, our study presented high heterogeneities in the majority of angiographic

and clinical outcomes, which were mainly driven by the TIS trial(15). The extensive inclusion criteria and

small including patients number induce more severe ISR lesions (regarding both minimal lumen diameter and

percent diameter stenosis) and frequently unfavorable pattern (regarding type of occlusion and proliferative)

allocated in the new-generation DES group (28-29). Compared with other including trails, the use of scoring

balloon catheters and implantation of another bail-out stent were more aggressive in TIS trial. The

proportion of usage of scoring balloon pre-dilation, which may have a potential role in improving the

anti-proliferation potency of DCB(30), were significant higher in the DCB group(15, 28). Therefore, further

researches with a careful follow-up protocol and large sample size should be performed to provide more

confirmative information.

Future perspectives

Currently, new-generation DES represents a superior treatment strategy with similar safety and improved

angiographic and clinical efficacy at short-term follow-up, which suggested a potential benefit of the use of

new-generation DES for coronary ISR. But both new-generation DES and DCB for the treatment of ISR are on

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the same class I (A) recommendation in the latest European Society of Cardiology guideline on myocardial

revascularization(1). Although new-generation DES reduce the possibility of recurrent ISR, the risk remains

high as multilayers of metal stents in the vessel wall will entail difficulty in further treatments and an

inherent poorer clinical prognosis(31). Bioresorbable scaffold (BRS) with proven safety and efficacy profiles

for ISR while avoiding in the mid-long term an additional metal layer may be an alternative treatment choice

in the future (32, 33). The ongoing AbsorbISR (Absorb Bioresorbable Scaffold vs. Drug Coated Balloon for

Treatment of In-Stent-Restenosis, NCT02474485) trial comparing bioresorbable vascular scaffold with DCB to

treat ISR will shed light in terms of clinical utility of BRS for coronary ISR. However for patients with

intolerable long-term dual antiplatelet therapy or high risk of bleeding, DCB may be more suitable.

Furthermore, researchers should pursue further optimization of DCB and its auxiliary strategy(34, 35), such

as use of scoring balloon before DCB (30).

Limitations


the trial level and shares the limitations of the original trials. Secondly, the studied DCB group included

Sequent PleaseTM

and Pantera LuxTM

paclitaxel-eluting balloons, which have different coatings design, as well

as the implemental methods of DCB in individual trials(10). Thirdly, the definitions of clinical and

angiographic parameters were not identical in some studies. Finally, in light of the fairly highly selected

criteria in our study, only a total of 913 patients were enrolled. However, our study demonstrates the largest

patient population presenting with ISR and is likely to remain the most powerful evidence base for evaluation

of DCB versus new-generation DES.

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Conclusions


angiographic and clinical efficacy compared to DCB for coronary ISR at short term follow-up. But either new

generation DES or DCB should be recommended as the first choice in the setting of patients with ISR still

relies on further larger scale, longer-term follow-up and randomized trials.

Contributors: ZYJ is the guarantor. ZYJ, CJZ, ZYX, WXY, ZH, BC, DXJ and IJ conceived the study design. CJZ,

ZYX, WXY, ZH and MA performed the report screening, study inclusion, data extraction. CP, MA, DXJ and ZH

analysis the data. ZYJ, CJZ, ZYX, WXY, BC, IJ, CP and MA drafted the manuscript. CP, MA, DXJ and ZH reviewed

the manuscript for important intellectual content. All authors have significantly contributed to the design of study,

analysis of data and drifting or revising manuscript. All authors have read and approved this article.


Department of Health [YKK15100], and Key Project of Nanjing Science and Technology Development

Foundation [201503024]. For the others authors none were declared.



References


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Figure legends

Figure 1


Figure 2






Figure 3



thrombosis.


Figure 4




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Figure 5






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Figure 1 Flow diagram of meta- analysis

191x165mm (300 x 300 DPI)

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254x190mm (300 x 300 DPI)

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254x190mm (300 x 300 DPI)

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254x124mm (300 x 300 DPI)

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254x185mm (300 x 300 DPI)

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1

Supplement

Figure 1

Title: Risk of bias


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Figure 2


Caption: The Egger’s liner regression tests for (A) target lesion revascularization, (B) target vessel revascularization, (C) major adverse cardiac events, (D)

myocardial infarction, (E) cardiac death, and (F) stent thrombosis.

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Study Age Male Hypertension Diabetes mellitus Dyslipidemia Previous MI Multi-vessel


TIS 66 (11) 66 (11) 43 (63) 46 (68) n/a n/a 17 (25) 18 (26) n/a n/a 43 (63) 41 (60) 38 (56) 41 (60)

RIBS IV 66 (10) 66 (10) 127 (82) 130 (84) 110 (71) 121 (78) 75 (49) 66 (43) 110 (71) 121 (78) 73 (47) 77 (50) n/a n/a

SEDUCE 68 (8) 64 (11) 18 (72) 25 (100) 16 (64) 15 (60) 6 (24) 1 (4) 24 (96) 24 (96) 12 (48) 10 (40) n/a n/a

RIBS V 67 (11) 64 (12) 82 (86) 82 (87) 68 (72) 68 (72) 30 (32) 19 (20) 69 (73) 62 (66) 57 (60) 56 (60) n/a n/a

BILUX RCT 67 (10) 69 (9) 122 (78) 49 (68) 144 (92) 70 (97) 48 (31) 24 (33) 134 (85) 62 (86) 93 (59) 35 (49) 95 (61) 39 (54)


Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; EES = everolimus-eluting stents; n/a = not available; MI = myocardial

infarction.

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TIS 23 (12) 19 (9) 10 (13) 18 (24) 72 (14) 78 (13) 0.92 (0.5) 0.79 (0.5) 2.64 (0.5) 2.66 (0.5)

RIBS IV 10 (6) 11 (5) 4 (3) 12 (8) 69 (17) 72 (15) 0.79 (0.4) 0.75 (0.4) 2.59 (0.5) 2.67 (0.5)

SEDUCE 20 (n/a) 18 (n/a) 4 (16) 6 (24) 68 (18) 79 (14) 0.98 (0.6) 0.57 (0.4) 3.0 (0.5) 2.85 (0.4)

RIBS V 14 (7) 14 (7) 12 (13) 18 (19) 61 (14) 65 (13) 1.02 (0.4) 0.93 (0.4) 2.64 (0.6) 2.64 (0.6)

BIOLUX RCT n/a n/a 20 (12) 12 (15) 67 (14) 69 (15) 1.0 (0.5) 0.9 (0.5) 3.0 (0.4) 2.9 (0.5)


Abbreviation: DCB = drug-coated balloon; DES = new-generation drug-eluting stents; DS = diameter stenosis; MLD = minimum lumen diameter; RVD = reference

vessel diameter; n/a = not available.

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Table 3 Search strategy for the Pubmed electronic database

#1 restenosis

#2 coronary

#3 #1 and #2

#4 eluting stent[Title/Abstract]

#5 eluting balloon[Title/Abstract]

#6 drug eluting balloon[Title/Abstract]

#7 #5 or #6

#8 #6 and #4

#9 #3 and #8

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TITLE


ABSTRACT


2

INTRODUCTION



3

METHODS





4


4




4


4



4-5




4-5

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Page 1 of 2



4-5


4-5

RESULTS


5-6


5-6



6-7




DISCUSSION


8-11


11


FUNDING


12



Page 2 of 2

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Journal: BMJ Open



Date Submitted by the Author: 09-Oct-2017

Complete List of Authors: Cai, Jin-Zan; Nanjing Medical University Zhu, Yong-Xiang ; Nanjing Medical University Wang, Xin-Yu; Xuzhou Cancer Hospital, Jiangsu University, Department of

Cardiology Bourantas, Christos ; University College London, Cardiovascular Sciences Iqbal, Javaid; Barts Heart Centre, Department of Cardiology Zhu, Hao; Nanjing Medical University Cummins, Paul ; Erasmus MC, Rotterdam, Department of Cardiology Dong, Sheng-Jie; Yantaishan hospital, Department of the Joint and Bone Surgery Mathur, Anthony; Barts Health NHS Trust, Cardiology zhang, yaojun; Xuzhou Cancer Hospital, Nanjing Medical University, Department of Cardiology






BMJ Open on M


http://bmjopen.bm

j.com/

BM



ownloaded from



1

Title page




1, MSc; Xin-Yu Wang


3, 4, PhD; Javaid





4, PhD; Yao-Jun

Zhang2* PhD



1Nanjing Medical University, Nanjing, China;

2Xuzhou Cancer Hospital, Nanjing Medical University, Nanjing, China;







*Correspondence to:




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Abstract

Objective: The study sought to compare angiographic and clinical outcomes of new-generation drug-eluting


Design: Meta-analysis using data from randomised trial found by searches on PubMed, the Cochrane Library,

Clinicaltrials.gov, and websites of major cardiovascular congresses.


Participants: Patients with ISR in the including trials.

Interventions: new-generation DES versus DCB.

Outcomes: The angiographic and clinical outcomes including cardiac death, all-cause death, myocardial


events (MACE), and stent thrombosis were investigated.

Results: Five trials including 913 patients were eligible and included. Pooled analysis in angiographic results


to -0.20, p<0.001) and lower % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04). DES significantly

reduced the risk of TLR (RR: 1.96, 95% CI: 1.17 to 3.28, p=0.01) compared with DCB; however there was no

statistical differences for MACE (RR: 1.21, 95% CI: 0.67 to 2.17, p=0.53), myocardial infarction (RR: 1.16, 95%

CI: 0.55 to 2.48, p=0.69), and cardiac death (RR: 1.80, 95% CI: 0.60 to 5.39, p=0.29).

Conclusions: Interventions with new-generation DES appears to be associated with significant reduction in %

diameter stenosis and TLR at short-term follow-up, but had similar MACE, myocardial infarction, and cardiac


are warranted to confirm these findings.


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meta-analysis.

2、、、、 This study includes the largest patient population presenting with ISR.

3、、、、 The results were based on the trial level and share the limitations of the original trials.

Introduction




5 years(2). Given the number of patients undergoing a stent implantation, which amounts to approximately

one million per annum in USA, ISR will continue to remain an undesirable adverse outcome(3).

The management of patients with ISR remains challenging. Currently, the treatment strategies for ISR mainly

include cutting balloon angioplasty, plain old balloon angioplasty, drug-coated balloon (DCB) and DES(4).

Several recent studies have reported that both new-generation DES and DCB are superior to other

interventional strategies for ISR(5-12). Moreover, recent guidelines on myocardial revascularization from the

European Society of Cardiology recommends DCB and new-generation DES (class I, level A) for patients

presenting with ISR(1). However, published literature comparing new-generation DES versus DCB in

randomized settings conclude with diverging results(8, 13-17). Additionally, these studies were constrained

by the small sample size. To overcome these limitation, we performed a meta-analysis of randomized

controlled trials to compare the clinical and angiographic outcomes results of new-generation DES versus

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DCB in patients with coronary ISR.

Methods



the Cochrane Library, and Clinicaltrials.gov as well as the websites of major cardiovascular congresses. The

subject keywords included coronary restenosis, drug-eluting balloon, paclitaxel-coated balloon, eluting

stent(s), and randomized trial were applied to identify studies. The last search was performed on September

12th, 2016 by two independent investigators (Cai JZ and Zhu YX). All studies comparing new-generation DES

versus DCB irrespective of patients presenting with any types of ISR were included.










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measure statistical heterogeneity among studies. An I2 > 50% was considered as significant heterogeneity. A


detected. Sensitivity analyses were carried out by excluding the studies with a high level of risk of bias, and

including only studies with a low proportion of missing data. We also repeated analyses in the subsets of

studies solely comparing paclitaxel-coated balloon versus everolimus-eluting stents, and patients only with

BMS-ISR. The Egger’s linear regression tests were employed to test for funnel plot asymmetry at the p<0.10

level of significance. However, the analysis for publication bias can only be tentative, as there is not enough

power to support the test results due to the limited number of studies included. All the statistical analyses

were performed using STATA Version 13.0 (Stata Corp., College Station, TX, USA) and Review Manager Version

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5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark).

Results


eligible and included(8, 13-17). The screening process is described in Figure 1. The median sample size were

189 (interquartile range 83-269). Only the TIS trial was single center, and the others were multicentre.

Patients enrolled were from Czech in TIS trial, Spain in RIBS IV and RIBS V trials, Belgium in SEDUCE trial, and

Germany and Latvia in BIOLUX RCT. All trial had a high risk of bias with respect to performance bias and the

details of methodology in BIOLUX RCT trial was not available. The summary of risk judgment in individual

trials is showed in Supplement Figure 1. The trial, patient and angiographic characteristics are summarized

(Table 1, Supplement Table 1 and 2). Apart from 229 patients (25.1%) with mixed types of ISR in 1 trial(17),

309 patients (33.9%) with DES-ISR were recruited in 1 trial(8), while 375 patients (41.0%) with BMS-ISR were

in 3 trials(14-16). The patients follow up ranged from 6 to 12 months angiographically, and 12 to 36 months

clinically.

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Table



e size

Definition

of ISR



Angiograph

ic Clinical DCB DES

TIS BMS SP


RIBS IV DES SP

PCB XP EES

154/15


SEDUCE BMS SP


RIBS V BMS SP


BILUX

RCT Both PL PCB

Orsiro

SES 157/72 n/a 6 12 n/a n/a


TLR






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8


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9






P=0.06; Figure 2B).









p=0.70; I2=0%, P=0.75; Figure 3C).




4A) and reduction of % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04; I2=72%, P=0.006; Figure 4B)

compared to DCB.

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DCB.




2=80%, P=0.0006; Figure




analyses suggested that DCB was associated with a high risk of MACE (RR: 1.57, 95% CI: 1.04 to 2.38, p=0.03;

I2=19%, P=0.29) as well as an increase in in MLD (-0.29 mm, 95% CI: -0.55 to -0.03, p=0.03; I

2=64%, P=0.04)

and binary restenosis (RR: 1.85, 95% CI: 1.11 to 3.10, p=0.02; I2=0%, P=0.99) while excluding the TIS trial

which come from single center. Detailed methodology in BIOLUX RCT trial was not available, however MLD

remained greater in DES group when the BIOLUX RCT trial was omitted (-0.29 mm, 95% CI: -0.55 to -0.04,

p=0.03; I2=60%, P=0.06).In the setting of patients with BMS-ISR(13, 15, 16), no significant differences were

found in DCB versus new-generation DES in all angiographic and clinical outcomes except for acute luminal

gain (-0.39 mm, 95% CI: -0.50 to -0.28, p<0.001; I2=0%, p=0.40).Patients treated exclusively with

everolimus-eluting stents had significant low incidence of TLR (RR: 2.64, 95% CI: 1.35 to 5.18, p=0.005;

I2=12%, P=0.32), increased acute luminal gain (-0.32 mm, 95% CI: -0.47 to -0.17, p<0.001; I

2=64%, P=0.04),

and superior MLD (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I2=60%, P=0.06;). But no statistical differences in

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other clinical and angiographic outcomes were observed between the 2 groups.

Discussion



showed that new-generation DES appears to be associated with an improved angiographic and clinical

outcomes when compared with DCB irrespective of the types of ISR at short term follow-up. The main

findings are as follows: (1) new generation DES were associated with a significant reduction in TLR compared

to DCB at the longest available follow-up; (2) there were no statistical differences in cardiac death,

myocardial infarction, and MACE between the two treatment strategies; (3) New-generation DES were

associated with favorable angiographic results with significant increase in acute luminal gain and reduction







clinical performance of different generation DES(21). ILiou et al. demonstrated no superiority of the

new-generation DES over DCB but their analysis included four observational studies in which an inequality of

baseline characteristics was observed(19). A further limitation of this meta-analysis was small number of

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randomized patients (n=548 from 3 RCTs)(19). Additionally, in a Bayesian network meta-analysis comparing

the performance of all therapeutic treatments for ISR, everolimus-eluting stent was considered as optimal

strategy with pronounced improvements in clinical outcomes6. However, the effect was mainly derived from

indirect comparison(5). In the present meta-analysis, we, for the first time, included only randomized trials of

new generation DES in comparison with DCB, so the possibility of confounders influencing estimates for

various endpoints is less likely. Furthermore, this meta-analysis included the largest number of ISR patients to

date and demonstrated that contemporary DES with improved design were associated with favorable

outcomes and a lower risk of re-intervention at mid-term follow-up, compared to DCB.











re-intervention. Although one may express concern regarding the long-term safety of stent implantation,


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biocompatibility or biodegradable polymer is extremely low(4, 21, 23). The present study, however, remains


is reasonable to assume that the short term (less than 1 year) benefit of new generation DES will remain

consistent.









on longer follow up. On the other hand, there were similar death in the EES group and DCB group from 1 to 3

years in the RIBS V trial. Thus, any potential long-term benefit of DCB compared with additional new

generation DES implantation remains unproven(27).

The studies included in this meta-analysis have several differences. Firstly, The RIBS IV trial contributed





Moreover, our study presented high heterogeneities in the majority of angiographic and clinical outcomes,

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which were mainly driven by the TIS trial(15). TIS trial had small sample size and extensive

inclusion/exclusion criteria(28-29). Furthermore, the use of scoring balloons and implantation of another

bail-out stent were more common in TIS trial, which may have a potential role in improving the

anti-proliferation potency of DCB(30). Further researches with a careful follow-up protocol and large sample

size should be performed to provide more confirmative information.

Future perspectives

Both new-generation DES and DCB for the treatment of ISR are on the same class I (A) recommendation in

the latest European Society of Cardiology guideline on myocardial revascularization(1). However, our

meta-analysis suggests that new-generation DES represent a superior treatment strategy with similar safety

and improved angiographic and clinical efficacy at short-term follow-up. Nevertheless, concerns remain

about multilayers of metal stents in the vessel wall which may entail difficulty in further treatments and an

inherent poorer clinical prognosis(31). Similarly, for patients with intolerable long-term dual antiplatelet

therapy or high risk of bleeding, DCB may be more suitable. Bioresorbable scaffold (BRS) may be an

alternative treatment choice in the future (32, 33). The ongoing AbsorbISR (Absorb Bioresorbable Scaffold vs.

Drug Coated Balloon for Treatment of In-Stent-Restenosis, NCT02474485) trial comparing bioresorbable

vascular scaffold with DCB to treat ISR will shed light in terms of clinical utility of BRS for coronary ISR. Finally,

further refinements in DCB technology and auxiliary strategies (34, 35), such as use of scoring balloon before

DCB (30), are warranted.

Limitations

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the trial level and shares the limitations of the original trials. Secondly, the studied DCB group included

Sequent PleaseTM

and Pantera LuxTM

paclitaxel-eluting balloons, which have different coatings design, as well

as the implemental methods of DCB in individual trials(10). Thirdly, the definitions of clinical and

angiographic parameters were not identical in some studies. Finally, in light of the fairly highly selected

criteria in our study, only a total of 913 patients were enrolled. However, our study demonstrates the largest

patient population presenting with ISR and is likely to remain the most powerful evidence base for evaluation

of DCB versus new-generation DES.

Conclusions


angiographic and clinical efficacy compared to DCB for coronary ISR at short term follow-up. Further larger

scale randomized trials with longer term follow-up are warranted.

Contributors: ZYJ is the guarantor. ZYJ, CJZ, ZYX, WXY, ZH, BC, DSJ and IJ conceived the study design. CJZ,

ZYX, WXY, ZH and MA performed the report screening, study inclusion, data extraction. CP, MA, DSJ and ZH

analysis the data. ZYJ, CJZ, ZYX, WXY, BC, IJ, CP and MA drafted the manuscript. CP, MA, DSJ and ZH reviewed




Department of Health [YKK15100], Key Project of Nanjing Science and Technology Development Foundation

[201503024], and six talent peaks project [WSN-212]. For the others authors none were declared.



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References


(Engl Ed) 2015;68:144.

























Suppl 1:624-9.



Interv 2016;9:1246-55.









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BMJ 2011;343:d5928.






































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Figure legends

Figure 1


Figure 2






Figure 3



thrombosis.


Figure 4




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Figure 5






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191x165mm (300 x 300 DPI)

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254x190mm (300 x 300 DPI)

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254x190mm (300 x 300 DPI)

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254x124mm (300 x 300 DPI)

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254x185mm (300 x 300 DPI)

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Supplement

Figure 1

Title: Risk of bias


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Figure 2


Caption: The Egger’s liner regression tests for (A) target lesion revascularization, (B) target vessel revascularization, (C) major adverse cardiac events, (D)

myocardial infarction, (E) cardiac death, and (F) stent thrombosis.

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TIS 66 (11) 66 (11) 43 (63) 46 (68) n/a n/a 17 (25) 18 (26) n/a n/a 43 (63) 41 (60) 38 (56) 41 (60)

RIBS IV 66 (10) 66 (10) 127 (82) 130 (84) 110 (71) 121 (78) 75 (49) 66 (43) 110 (71) 121 (78) 73 (47) 77 (50) n/a n/a

SEDUCE 68 (8) 64 (11) 18 (72) 25 (100) 16 (64) 15 (60) 6 (24) 1 (4) 24 (96) 24 (96) 12 (48) 10 (40) n/a n/a

RIBS V 67 (11) 64 (12) 82 (86) 82 (87) 68 (72) 68 (72) 30 (32) 19 (20) 69 (73) 62 (66) 57 (60) 56 (60) n/a n/a

BILUX RCT 67 (10) 69 (9) 122 (78) 49 (68) 144 (92) 70 (97) 48 (31) 24 (33) 134 (85) 62 (86) 93 (59) 35 (49) 95 (61) 39 (54)



infarction.

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TIS 23 (12) 19 (9) 10 (13) 18 (24) 72 (14) 78 (13) 0.92 (0.5) 0.79 (0.5) 2.64 (0.5) 2.66 (0.5)

RIBS IV 10 (6) 11 (5) 4 (3) 12 (8) 69 (17) 72 (15) 0.79 (0.4) 0.75 (0.4) 2.59 (0.5) 2.67 (0.5)

SEDUCE 20 (n/a) 18 (n/a) 4 (16) 6 (24) 68 (18) 79 (14) 0.98 (0.6) 0.57 (0.4) 3.0 (0.5) 2.85 (0.4)

RIBS V 14 (7) 14 (7) 12 (13) 18 (19) 61 (14) 65 (13) 1.02 (0.4) 0.93 (0.4) 2.64 (0.6) 2.64 (0.6)

BIOLUX RCT n/a n/a 20 (12) 12 (15) 67 (14) 69 (15) 1.0 (0.5) 0.9 (0.5) 3.0 (0.4) 2.9 (0.5)




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#1 restenosis

#2 coronary

#3 #1 and #2




#7 #5 or #6

#8 #6 and #4

#9 #3 and #8

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TITLE


ABSTRACT


2

INTRODUCTION



3

METHODS





4


4




4


4



4-5




4-5

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4-5


4-5

RESULTS


5-6


5-6



6-7




DISCUSSION


8-11


11


FUNDING


12



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Journal: BMJ Open



Date Submitted by the Author: 22-Jan-2018

Complete List of Authors: Cai, Jin-Zan; Nanjing Medical University Zhu, Yong-Xiang ; Nanjing Medical University Wang, Xin-Yu; Xuzhou Cancer Hospital, Jiangsu University, Department of

Cardiology Bourantas, Christos ; University College London, Cardiovascular Sciences Iqbal, Javaid; Barts Heart Centre, Department of Cardiology Zhu, Hao; Nanjing Medical University Cummins, Paul ; Erasmus MC, Rotterdam, Department of Cardiology Dong, Sheng-Jie; Yantaishan hospital, Department of the Joint and Bone Surgery Mathur, Anthony; Barts Health NHS Trust, Cardiology zhang, yaojun; Xuzhou Cancer Hospital, Nanjing Medical University, Department of Cardiology






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Title page




1, MSc; Xin-Yu Wang


3, 4, PhD; Javaid





4, PhD; Yao-Jun

Zhang2* PhD



1Nanjing Medical University, Nanjing, China;

2Xuzhou Cancer Hospital, Nanjing Medical University, Nanjing, China;







*Correspondence to:




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Abstract

Objective: The study sought to compare angiographic and clinical outcomes of new-generation drug-eluting


Design: Meta-analysis using data from randomised trial found by searches on PubMed, the Cochrane Library,

Clinicaltrials.gov, and websites of major cardiovascular congresses.


Participants: Patients with ISR in the including trials.

Interventions: new-generation DES versus DCB.

Outcomes: The angiographic and clinical outcomes including cardiac death, all-cause death, myocardial


events (MACE), and stent thrombosis were investigated.

Results: Five trials including 913 patients were eligible and included. Pooled analysis in angiographic results


to -0.20, p<0.001) and lower % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04). DES significantly

reduced the risk of TLR (RR: 1.96, 95% CI: 1.17 to 3.28, p=0.01) compared with DCB; however there was no

statistical differences for MACE (RR: 1.21, 95% CI: 0.67 to 2.17, p=0.53), myocardial infarction (RR: 1.16, 95%

CI: 0.55 to 2.48, p=0.69), and cardiac death (RR: 1.80, 95% CI: 0.60 to 5.39, p=0.29).

Conclusions: Interventions with new-generation DES appears to be associated with significant reduction in %

diameter stenosis and TLR at short-term follow-up, but had similar MACE, myocardial infarction, and cardiac


are warranted to confirm these findings.


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- Only randomized trials comparing DES with DCB for patients with ISR were allowed to include in this

meta-analysis.

- This study includes the largest patient population presenting with ISR.

- The results were based on the trial level and share the limitations of the original trials.

Introduction




5 years(2). Given the number of patients undergoing a stent implantation, which amounts to approximately

one million per annum in USA, ISR will continue to remain an undesirable adverse outcome(3).

The management of patients with ISR remains challenging. Currently, the treatment strategies for ISR mainly

include cutting balloon angioplasty, plain old balloon angioplasty, drug-coated balloon (DCB) and DES(4).

Several recent studies have reported that both new-generation DES and DCB are superior to other

interventional strategies for ISR(5-12). Moreover, recent guidelines on myocardial revascularization from the

European Society of Cardiology recommends DCB and new-generation DES (class I, level A) for patients

presenting with ISR(1). However, published literature comparing new-generation DES versus DCB in

randomized settings conclude with diverging results(8, 13-17). Additionally, these studies were constrained

by the small sample size. To overcome these limitation, we performed a meta-analysis of randomized

controlled trials to compare the clinical and angiographic outcomes results of new-generation DES versus

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DCB in patients with coronary ISR.

Methods



the Cochrane Library, and Clinicaltrials.gov as well as the websites of major cardiovascular congresses. The

subject keywords included coronary restenosis, drug-eluting balloon, paclitaxel-coated balloon, eluting

stent(s), and randomized trial were applied to identify studies (Supplement Table 1). The last search was

performed on September 12th, 2016 by two independent investigators (Cai JZ and Zhu YX). All studies

comparing new-generation DES versus DCB irrespective of patients presenting with any types of ISR were

included.









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measure statistical heterogeneity among studies. An I2 > 50% was considered as significant heterogeneity. A


detected. Sensitivity analyses were carried out by excluding the studies with a high level of risk of bias, and

including only studies with a low proportion of missing data. We also repeated analyses in the subsets of

studies solely comparing paclitaxel-coated balloon versus everolimus-eluting stents, and patients only with

BMS-ISR. The Egger’s linear regression tests were employed to test for funnel plot asymmetry at the p<0.10

level of significance. However, the analysis for publication bias can only be tentative, as there is not enough

power to support the test results due to the limited number of studies included. All the statistical analyses

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were performed using STATA Version 13.0 (Stata Corp., College Station, TX, USA) and Review Manager Version

5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark).

Results


eligible and included(8, 13-17). The screening process is described in Figure 1. The median sample size were

189 (interquartile range 83-269). Only the TIS trial was single center, and the others were multicentre.

Patients enrolled were from Czech in TIS trial, Spain in RIBS IV and RIBS V trials, Belgium in SEDUCE trial, and

Germany and Latvia in BIOLUX RCT. All trial had a high risk of bias with respect to performance bias and the

details of methodology in BIOLUX RCT trial was not available. The summary of risk judgment in individual

trials is showed in Supplement Figure 1. The trial, patient and angiographic characteristics are summarized

(Table 1, Supplement Table 2 and 3). Apart from 229 patients (25.1%) with mixed types of ISR in 1 trial(17),

309 patients (33.9%) with DES-ISR were recruited in 1 trial(8), while 375 patients (41.0%) with BMS-ISR were

in 3 trials(14-16). The patients follow up ranged from 6 to 12 months angiographically, and 12 to 36 months

clinically.

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Table


Study Type Treatment arms Sample

size

Definition

of ISR

Follow-up, months DAPT, months

Definition of MACE Angiographi

c Clinical DCB DES

TIS BMS SP PCB PE EES 68/68 ≥50% DS 12 12 3 6-12 Death, any MI, and TVR

RIBS IV DES SP PCB XP EES 154/155 ≥50% DS 9 12 3 12 Death, MI, and TLR

SEDUCE BMS SP PCB XP EES 25/25 >70% DS 9 12 n/a n/a n/a

RIBS V BMS SP PCB XP EES 95/94 ≥50% DS 9 36 3 12 Death, MI, and TLR

BILUX RCT Both PL PCB Orsiro SES 157/72 n/a 6 12 n/a n/a Cardiac death, MI, and TLR

Abbreviations: BMS = bare-metal stents; CAG = coronary angiography; DAPT = dual antiplatelet therapy; DCB = drug-eluting balloon;

DES = drug-eluting stents; DS=diameter stenosis; ISR=in-stent restenosis; MACE = major adverse cardiac events; MI = myocardial

infarction; n/a = not available; PE EES = Promus Element everolimus-eluting stents; PL PCB = Pantera Lux paclitaxel-coated balloon; SES =

sirolimus-eluting balloon; SP PCB = SeQuent Please paclitaxel-coated balloon; TLR = target lesion revascularization; TVR = target vessel

revascularization; XP EES = Xience Prime everolimus-eluting stent.

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8






P=0.06; Figure 2B).









p=0.70; I2=0%, P=0.75; Figure 3C).




4A) and reduction of % diameter stenosis (RR: 0.28, 95% CI: 0.02 to 0.55, p=0.04; I2=72%, P=0.006; Figure 4B)

compared to DCB.

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DCB.




2=80%, P=0.0006; Figure




analyses suggested that DCB was associated with a high risk of MACE (RR: 1.57, 95% CI: 1.04 to 2.38, p=0.03;

I2=19%, P=0.29) as well as an increase in in MLD (-0.29 mm, 95% CI: -0.55 to -0.03, p=0.03; I

2=64%, P=0.04)

and binary restenosis (RR: 1.85, 95% CI: 1.11 to 3.10, p=0.02; I2=0%, P=0.99) while excluding the TIS trial

which come from single center. Detailed methodology in BIOLUX RCT trial was not available, however MLD

remained greater in DES group when the BIOLUX RCT trial was omitted (-0.29 mm, 95% CI: -0.55 to -0.04,

p=0.03; I2=60%, P=0.06).In the setting of patients with BMS-ISR(13, 15, 16), no significant differences were

found in DCB versus new-generation DES in all angiographic and clinical outcomes except for acute luminal

gain (-0.39 mm, 95% CI: -0.50 to -0.28, p<0.001; I2=0%, p=0.40).Patients treated exclusively with

everolimus-eluting stents had significant low incidence of TLR (RR: 2.64, 95% CI: 1.35 to 5.18, p=0.005;

I2=12%, P=0.32), increased acute luminal gain (-0.32 mm, 95% CI: -0.47 to -0.17, p<0.001; I

2=64%, P=0.04),

and superior MLD (-0.29 mm, 95% CI: -0.55 to -0.04, p=0.03; I2=60%, P=0.06;). But no statistical differences in

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other clinical and angiographic outcomes were observed between the 2 groups.

Discussion



showed that new-generation DES appears to be associated with an improved angiographic and clinical

outcomes when compared with DCB irrespective of the types of ISR at short term follow-up. The main

findings are as follows: (1) new generation DES were associated with a significant reduction in TLR compared

to DCB at the longest available follow-up; (2) there were no statistical differences in cardiac death,

myocardial infarction, and MACE between the two treatment strategies; (3) New-generation DES were

associated with favorable angiographic results with significant increase in acute luminal gain and reduction







clinical performance of different generation DES(21). ILiou et al. demonstrated no superiority of the

new-generation DES over DCB but their analysis included four observational studies in which an inequality of

baseline characteristics was observed(19). A further limitation of this meta-analysis was small number of

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randomized patients (n=548 from 3 RCTs)(19). Additionally, in a Bayesian network meta-analysis comparing

the performance of all therapeutic treatments for ISR, everolimus-eluting stent was considered as optimal

strategy with pronounced improvements in clinical outcomes6. However, the effect was mainly derived from

indirect comparison(5). In the present meta-analysis, we, for the first time, included only randomized trials of

new generation DES in comparison with DCB, so the possibility of confounders influencing estimates for

various endpoints is less likely. Furthermore, this meta-analysis included the largest number of ISR patients to

date and demonstrated that contemporary DES with improved design were associated with favorable

outcomes and a lower risk of re-intervention at mid-term follow-up, compared to DCB.











re-intervention. Although one may express concern regarding the long-term safety of stent implantation,


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biocompatibility or biodegradable polymer is extremely low(4, 21, 23). The present study, however, remains


is reasonable to assume that the short term (less than 1 year) benefit of new generation DES will remain

consistent.









on longer follow up. On the other hand, there were similar death in the EES group and DCB group from 1 to 3

years in the RIBS V trial. Thus, any potential long-term benefit of DCB compared with additional new

generation DES implantation remains unproven(27).

The studies included in this meta-analysis have several differences. Firstly, The RIBS IV trial contributed





Moreover, our study presented high heterogeneities in the majority of angiographic and clinical outcomes,

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which were mainly driven by the TIS trial(15). TIS trial had small sample size and extensive

inclusion/exclusion criteria(28-29). Furthermore, the use of scoring balloons and implantation of another

bail-out stent were more common in TIS trial, which may have a potential role in improving the

anti-proliferation potency of DCB(30). Further researches with a careful follow-up protocol and large sample

size should be performed to provide more confirmative information.

Future perspectives

Both new-generation DES and DCB for the treatment of ISR are on the same class I (A) recommendation in

the latest European Society of Cardiology guideline on myocardial revascularization(1). However, our

meta-analysis suggests that new-generation DES represent a superior treatment strategy with similar safety

and improved angiographic and clinical efficacy at short-term follow-up. Nevertheless, concerns remain

about multilayers of metal stents in the vessel wall which may entail difficulty in further treatments and an

inherent poorer clinical prognosis(31). Similarly, for patients with intolerable long-term dual antiplatelet

therapy or high risk of bleeding, DCB may be more suitable. Bioresorbable scaffold (BRS) may be an

alternative treatment choice in the future (32, 33). The ongoing AbsorbISR (Absorb Bioresorbable Scaffold vs.

Drug Coated Balloon for Treatment of In-Stent-Restenosis, NCT02474485) trial comparing bioresorbable

vascular scaffold with DCB to treat ISR will shed light in terms of clinical utility of BRS for coronary ISR. Finally,

further refinements in DCB technology and auxiliary strategies (34, 35), such as use of scoring balloon before

DCB (30), are warranted.

Limitations

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the trial level and shares the limitations of the original trials. Specially, the clinical outcomes of TLR, TVR and

MACE were only reported in four trials respectively, which may, in some degree, affect the outcomes of this

meta-analysis. Secondly, the studied DCB group included Sequent PleaseTM

and Pantera LuxTM

paclitaxel-eluting balloons, which have different coatings design, as well as the implemental methods of DCB

in individual trials(10). Thirdly, the definitions of clinical and angiographic parameters were not identical in

some studies. Finally, in light of the fairly highly selected criteria in our study, only a total of 913 patients

were enrolled. However, our study demonstrates the largest patient population presenting with ISR and is

likely to remain the most powerful evidence base for evaluation of DCB versus new-generation DES.

Conclusions


angiographic and clinical efficacy compared to DCB for coronary ISR at short term follow-up. Further larger

scale randomized trials with longer term follow-up are warranted.

Contributors: ZYJ is the guarantor. ZYJ, CJZ, ZYX, WXY, ZH, BC, DSJ and IJ conceived the study design. CJZ,

ZYX, WXY, ZH and MA performed the report screening, study inclusion, data extraction. CP, MA, DSJ and ZH

analysis the data. ZYJ, CJZ, ZYX, WXY, BC, IJ, CP and MA drafted the manuscript. CP, MA, DSJ and ZH reviewed




Department of Health [YKK15100], Key Project of Nanjing Science and Technology Development Foundation

[201503024], and six talent peaks project [WSN-212]. For the others authors none were declared.



References


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(Engl Ed) 2015;68:144.

























Suppl 1:624-9.



Interv 2016;9:1246-55.














BMJ 2011;343:d5928.

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Figure legends

Figure 1


Figure 2



and (C) MACE.

Abbreviations: DCB = drug-coated balloon; DES = drug-eluting stents; MACE = major adverse cardiac events;

TLR = target lesion revascularization; TVR= target vessel revascularization.

Figure 3




Figure 4


Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) acute lumen

gain, and (B) % DS.


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Figure 5


Caption: Size of data markers indicates weight of each trial included in the meta-analysis: (A) MLD, (B) binary

restenosis, and (C) LLL.

Abbreviation: DCB = drug-coated balloon; DES = drug-eluting stents; MLD = minimum lumen diameter; LLL =

late lumen loss.

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191x165mm (300 x 300 DPI)

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254x190mm (300 x 300 DPI)

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254x190mm (300 x 300 DPI)

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254x124mm (300 x 300 DPI)

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254x185mm (300 x 300 DPI)

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Supplement

Figure 1

Title: Risk of bias

Caption: Proportions of studies classified as having low (green), unclear (yellow), and high (red)

risk of bias across domains of study quality.

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Figure 2


Caption: The Egger’s liner regression tests for (A) target lesion revascularization, (B) target

vessel revascularization, (C) major adverse cardiac events, (D) myocardial infarction, (E)

cardiac death, and (F) stent thrombosis.

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#1 restenosis

#2 coronary

#3 #1 and #2




#7 #5 or #6

#8 #6 and #4

#9 #3 and #8

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TIS 66 (11) 66 (11) 43 (63) 46 (68) n/a n/a 17 (25) 18 (26) n/a n/a 43 (63) 41 (60) 38 (56) 41 (60)

RIBS IV 66 (10) 66 (10) 127 (82) 130 (84) 110 (71) 121 (78) 75 (49) 66 (43) 110 (71) 121 (78) 73 (47) 77 (50) n/a n/a

SEDUCE 68 (8) 64 (11) 18 (72) 25 (100) 16 (64) 15 (60) 6 (24) 1 (4) 24 (96) 24 (96) 12 (48) 10 (40) n/a n/a

RIBS V 67 (11) 64 (12) 82 (86) 82 (87) 68 (72) 68 (72) 30 (32) 19 (20) 69 (73) 62 (66) 57 (60) 56 (60) n/a n/a

BILUX RCT 67 (10) 69 (9) 122 (78) 49 (68) 144 (92) 70 (97) 48 (31) 24 (33) 134 (85) 62 (86) 93 (59) 35 (49) 95 (61) 39 (54)



infarction.

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TIS 23 (12) 19 (9) 10 (13) 18 (24) 72 (14) 78 (13) 0.92 (0.5) 0.79 (0.5) 2.64 (0.5) 2.66 (0.5)

RIBS IV 10 (6) 11 (5) 4 (3) 12 (8) 69 (17) 72 (15) 0.79 (0.4) 0.75 (0.4) 2.59 (0.5) 2.67 (0.5)

SEDUCE 20 (n/a) 18 (n/a) 4 (16) 6 (24) 68 (18) 79 (14) 0.98 (0.6) 0.57 (0.4) 3.0 (0.5) 2.85 (0.4)

RIBS V 14 (7) 14 (7) 12 (13) 18 (19) 61 (14) 65 (13) 1.02 (0.4) 0.93 (0.4) 2.64 (0.6) 2.64 (0.6)

BIOLUX RCT n/a n/a 20 (12) 12 (15) 67 (14) 69 (15) 1.0 (0.5) 0.9 (0.5) 3.0 (0.4) 2.9 (0.5)




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TITLE


ABSTRACT


2

INTRODUCTION



3

METHODS





4


4




4


4



4-5




4-5

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Page 1 of 2



4-5


4-5

RESULTS


5-6


5-6



6-7




DISCUSSION


8-11


11


FUNDING


12



Page 2 of 2

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BMJ Open

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bmj open€¦ · for peer review only 17 6. unverdorben m, vallbracht c, cremers b, et al....

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